Project Summary/Abstract A more thorough understanding of human brain function has profound implications for advancing neuroscience research and combatting neurological disease. Despite tremendous progress towards this goal through contemporary neuroimaging techniques, a number of challenges remain unaddressed, such as a lack of safe and non-invasive imaging modalities for continuous brain function assessments, limited spatiotemporal resolution in in vivo imaging of human brain dynamics, and suboptimal accuracy due to improper consideration of complex 3D brain anatomy. Moreover, human brain functions exhibit complex and hierarchical patterns ranging from basic motor/sensory responses to advanced cognitive processes. Restricted by the poor portability of fMRI, MEG, and PET, as well as the low spatial resolution in EEG, conventional neuroimaging paradigms predominantly involve in-lab experiments with limited types of stimuli and interactions. This limited exploration of brain functions hinders our progress in understanding the brain. As strongly echoed in the BRAIN 2025 Scientific Vision, innovations in flexible, wearable and quantitative neuroimaging techniques that impose minimal restrictions to the subject will enable studies of advanced brain dynamics that are only apparent when measured in a natural environment. In the past decade, an emerging neuroimaging technique ? functional near-infrared spectroscopy (fNIRS) ? has shown great promise for safe and long-term monitoring of brain activity using low-power light. However, most existing fNIRS systems require the use of a headgear attached to a cart-sized optical unit via numerous and fragile optical fibers and output only topographic (instead of tomographic) images of limited spatial resolution. These limitations greatly hinder fNIRS?s widespread use. In this proposal, we aim to advance optical brain imaging to the next generation by developing a wireless, ultra-portable, modular, and fiberless advanced optical brain imaging platform (AOBI). By using innovative flexible-circuit based modular optical circuits, the proposed imaging system is light-weight, wearable, and safe for long-term monitoring. Our specific aims are 1) develop full-head-conforming 3D- aware optical brain imaging headgear using flex-circuit and reconfigurable optical modules, 2) develop high- resolution optical brain image processing pipelines using prior-guided reconstruction algorithms, and 3) run a small-scale clinical validation (N=15) to show proof-of-concept of monitoring post-stroke rehabilitation using the proposed system. If successfully developed, the proposed AOBI imaging platform will deliver several orders of magnitude reduction in cost and weight, 5 to 10-fold higher in imaging contrast, and 2-3 times better in resolution compared to conventional fNIRS techniques. This new platform may play an important role in monitoring post-stroke rehabilitation, assessing visual impairment, intracranial hypertension, insomnia, depression, head injuries, and behavioral disorders such as schizophrenia, bipolar, and post-traumatic stress.